Conditionally silencing the activity of specific neural ensembles is a powerful approach for mapping brain circuits responsible for specific behaviors. While microbial opsin- based tools exist to silence neural activity with light, these tools have significant limitations that make them unsuitable for persistent silencing over the course of minutes or hours. Longer term neuronal silencing has been classically achieved by expressing the catalytic light chain of Clostridium neurotoxins, which disrupt neurotransmitter release, however this approach suffers from poor temporal and spatial control. Recent chemogenetic approaches have been developed for persistent silencing, but lack the spatiotemporal benefits of optogenetic approaches and can be limited by off-target pharmacology. Thus, there remains an unmet need for silencing tools that combine the robust and persistent silencing qualities of chemogenetic tools and Clostridium neurotoxins, with the spatiotemporal control of optogenetics. We will develop a versatile approach for rapid, extended neural silencing that can be actuated by single/multiphoton excitation or with a small molecule, offering spatial control ranging from individual synapses to whole animals. Our approach will not only be applicable to neurotransmitter systems, but also to neuromodulatory systems and glial transmission. Because our strategy operates on a completely different principle than current tools, it could be multiplexed with existing approaches for complex remote control of neural circuit activity during behavior.